rs201945078

Positions:

• chr19-10160043-C-G
• chr19-10160043-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001130823.3(DNMT1):​c.1064G>C​(p.Arg355Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.293

Genes affected

DNMT1 (HGNC:2976): (DNA methyltransferase 1) This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNMT1. . Gene score misZ 4.9903 (greater than the threshold 3.09). Trascript score misZ 7.3302 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory neuropathy-deafness-dementia syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0064425766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1064G>C	p.Arg355Pro	missense_variant	15/41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1016G>C	p.Arg339Pro	missense_variant	14/40		NP_001305659.1
DNMT1	NM_001379.4	c.1016G>C	p.Arg339Pro	missense_variant	14/40		NP_001370.1
DNMT1	NM_001318731.2	c.701G>C	p.Arg234Pro	missense_variant	15/41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1064G>C	p.Arg355Pro	missense_variant	15/41	1	NM_001130823.3	ENSP00000352516

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000260 AC: 379 AN: 1459466 Hom.: 0 Cov.: 31 AF XY: 0.000247 AC XY: 179 AN XY: 726068

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000900

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00482

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome Cov.: 32

ExAC AF: 0.00611 AC: 741

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.20
Sift	Benign	0.26	T;T
Sift4G	Benign	0.086	T;T
Polyphen		0.0010	B;B
Vest4		0.56
MVP		0.94
MPC		0.98
ClinPred		0.0085	T
GERP RS		0.69
Varity_R		0.12
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201945078; hg19: chr19-10270719; COSMIC: COSV61583811; COSMIC: COSV61583811;